Synthetic lethality from combination of JAK and PARP inhibitors in MPN. Dysregulated JAK signaling from mutation of JAK2, MPL, or CALR leads to enhanced signaling through downstream pathways such as STATs, MAP kinase, and PI3K/AKT, which are well known to activate cell proliferation and survival programs. It has also recently been shown that this dysregulated JAK signaling leads to increased levels of ROS, which stall DNA replication forks and lead to increased levels of DNA double-strand breaks. These findings have been exploited to show that JAK inhibition lowers levels of DNA repair pathways, particularly BRCA-dependent HRR and D-NHEJ, which are important for DNA double-strand break repair and, in doing so, creates a synthetic lethal sensitivity to PARP inhibitors. This JAK/PARP inhibitor combination is sufficient to eliminate quiescent and proliferating MPN leukemic stem progenitor cells in vitro and in vivo.